Oral squamous cell carcinoma of the head and neck (OSCC) is the sixth most common cancer in the United States. Development of more targeted therapies is needed to reduce the high mortality rate seen with this cancer. Epidermal Growth Factor Receptor (EGFR) has emerged as a plausible therapeutic target for OSCC. Overexpression of this tyrosine kinase receptor has been characterized in OSCC and found to be present in up to ~90% of tumors where expression levels correlate with decreased patient survival. In 2006 cetuximab (Erbitux;Imclone Systems) (an EGFR specific monoclonal antibody) became the first new FDA-approved treatment for SCCHN in 45 years. Despite ubiquitous EGFR expression in OSCC, cetuximab has demonstrated limited clinical responses as a single agent (~10%). One potential mechanism of resistance to the wild type EGFR blockade is the expression of the constitutively active EGF receptor variant 3 (EGFRvIII). Sok et al. (2006) reported the presence of EGFRvIII in approximately 40% of SCCHN, and demonstrated in vitro and in vivo resistance of EGFRvIII expressing cells to cetuximab. In glioma (where EGFRvIII has been best characterized) STAT3 and Src family kinases (SFKs) have been elucidated as key regulatory proteins in the oncogenic phenotype of EGFRvIII. The mechanism of EGFRvIII protein expression is still unexplored in OSCC. Additionally, differential signaling pathways mediated through EGFRvIII remain relatively uncharacterized in SCCHN. I hypothesize that the mechanism contributing to EGFRvIII expression in OSCC is alteration of the mRNA splice sites for exons 2-7 causing alternate splicing of the EGFR transcript. Further, I hypothesize that EGFRvIII specific signaling through STAT3 and SFKs contributes to the oncogenic phenotype of EGFRvIII and that blocking these regulatory elements will lead to enhanced response to EGFR targeting agents. PUBLIC HEALTH RELEVANCE: OSCC is a devastating disease with high mortality and morbidity. Current treatments for OSCC are still limited with many patients demonstrating resistance to treatment. The work proposed here will elucidate a more thorough understanding of the pathways of therapeutic resistance and facilitate the design of more effective treatment regimens.